Visna virus, a non-oncogenic retrovirus, is the etiologic agent of a slow demyelinating disease of sheep. The virus causes a lifelong persistent infection in the animal. Inoculated sheep develop vigorous immune responses which fail to cure the infection. The presence of virus specific DNA in the tissue of infected animals may provide a mechanism for viral persistence, but it does not explain the continued expression of infectious virus as well as chronic progressive disease in the presence of neutralizing antibody. Recent studies from our laboratory have implicated progressive antigenic drift as a mechanism for chronic disease. Antigenically distinct viruses were detected in leukocytes of an experimentally inoculated sheep at 10 months post-inoculation, whereas viruses isolated prior to this time were of parental antigenic phenotype. Different antigenic variants were isolated for up to four years with the sequential development of neutralizing antibody against these evolving variants. Initial studies of these antigenic variants isolated from a persistently infected sheep have demonstrated multiple mutations in the 3' terminal region of the viral RNAs of these mutants. By analogy to the other retrovirus systems this is the region which codes for the envelope glycoprotein gene. To understand the molecular events which result in antigenic variation of visna virus we plan first to genetically map the envelope glycoprotein gene. This is most likely the location of genetic changes which involve virus neutralization. Once the boundaries of the envelope gene has been determined, we will use monoclonal antibodies directed against this protein to select mutants which would be expected to contain mutations in a region of the genome which affects the glycoprotein gene and more specifically the region involved in virus neutralization. Analysis of the genomes of these mutants should locate the regions which code for the antigenic determinants of the glycoprotein molecule involved in neutralization. Finally, studies on the structure of the envelope glycoprotein and the consequences of antigenic variation on this structure should provide us with an understanding of the mechanism of antigenic variation at the molecular level.